Overall, vitamin D gets pretty good press; the trouble is that hard evidence to back up the vitamin's -- or should we say prohormone's -- benefits is lacking.

Vitamin D is good for what ails you. Or at least that's what patients and doctors might conclude if they read only the headlines.

In the past few months, deficiency in the substance has been linked to chronic obstructive pulmonary disease, tuberculosis, spinal inflammatory diseases, age-related macular degeneration ... and the list goes on.

On the other hand, taking high doses of vitamin D didn't help patients with multiple sclerosis, MedPage Today reported, and it was of no benefit in reducing left ventricular mass in patients with chronic kidney disease.

But overall, vitamin D gets pretty good press. The trouble is that hard evidence to back up the vitamin's benefits is lacking, according to Clifford Rosen, MD, of the Maine Medical Center Research Institute in Scarborough. "There's no data," Rosen told MedPage Today. "It's all weak association studies."

Benefit Beyond the Bones

At the American Heart Association meeting earlier this month, several studies suggested associations between low vitamin D and various aspects of heart disease.

But as one observer said at the time, there are no clinical trials yet that show improving vitamin D status does anything to reduce cardiovascular risk.

One study, the Vitamin D and Omega-3 (VITAL) trial, may shed some light on the issue. It is a randomized trial that is enrolling some 20,000 patients to see if daily vitamin D supplements prevent cancer and cardiovascular disease.

It will be one of the few randomized trials -- if not the only one -- to look at the issue directly, according to JoAnn Manson, MD, of Brigham and Women's Hospital in Boston, who is the principal investigator.

Although other randomized trials have produced evidence for a vitamin D benefit in several important clinical categories, Manson told MedPage Today it was mostly as an afterthought.

"Many of the randomized trials people have heard about were trials designed to look at the effect of vitamin D on fractures and falls," she said, with other effects as secondary outcomes.

It's in the nature of statistics, she pointed out, that if researchers look at enough outcomes, some will be significant just on the basis of chance.

The vast mass of the evidence for any kind of nonskeletal benefit is observational, and therefore suspect until confirmed by a properly designed, randomized trial, Manson said.

Among other things, a host of confounding factors -- obesity, poor nutrition, lack of exercise -- might play a role. No matter how carefully an observational study is done, she said, confounding is always possible. "Correlation does not prove causation," Manson reminded.

She noted that randomized trials have demolished observational evidence many times in the past, notably in the cases of such former fads as beta-carotene and selenium.

According to Rosen, there is reasonable evidence that improved vitamin D status leads to better bone health and some evidence that supplements reduce all-cause mortality in elderly women.

For almost everything else, he said, hard evidence is missing.

Biologically Active D

Measuring exposure to vitamin D is relatively easy -- it's a simple matter of serum levels of a compound called 25-hydroxyvitamin D, or 25(OH)D, Rosen said.

But the relationship between circulating 25(OH)D and the active form of the vitamin, 1,25-dihydroxycholecalciferol, is not clear. It's entirely possible, he said, to have low levels of 25(OH)D and yet have a perfectly adequate amount of the hormonally active form.

Indeed, Manson said, the Institute of Medicine (IOM) recently estimated that the average requirement of 25(OH)D is really only 16 nanograms per milliliter -- a level that would in most cases ensure adequate amounts of the active vitamin.

"It's extremely variable," she noted, "and there is much that isn't known about vitamin D and metabolism."

"So the tissues and cells may be seeing adequate amounts of biological active vitamin D and adequate stimulation of the vitamin D receptor even in those who have lower blood levels," she said.

So the question of how much vitamin D is enough is a vexing one. But doctors and their patients still want an answer.

The IOM last year released new guidelines for vitamin D, which say that healthy people should aim to have at least 20 nanograms of 25(OH)D per milliliter of serum.

That can be achieved, the IOM said, by taking 600 IU a day of a vitamin D supplement if people are between ages 1 and 70, and 800 a day if they are 70 or older.

Manson, who along with Rosen was part of the IOM panel, said that "relatively modest amount" of vitamin D will keep 97.5% of the general population in good bone health.

And, she noted, the IOM really was only concerned about bone health, because there's such a dearth of evidence for benefits in other areas.

But even if there's no evidence for a benefit, is there any harm in taking a bit extra? Well, possibly.

One of the functions of vitamin D is to regulate calcium and phosphorus; too much can lead to hypercalcemia. The IOM set the tolerable upper limit at between 2,500 and 4,000 IU per day, depending on age.

The institute also cautioned, Manson said, that there is some evidence of a U-shaped curve for vitamin D -- too little is bad and so is too much.

In particular, the IOM reported that, although the evidence is weak, more than 4,000 IU a day of the vitamin might increase the risk of cardiovascular disease, some cancers, and all-cause mortality.

"There's no evidence that more is better, so why use more?" Rosen asked.

On a day to day basis, most people can ensure they have enough vitamin D by eating certain foods – fatty fish like salmon, for example – and taking a multivitamin, Manson said.

But there's no need to screen the healthy population for vitamin D levels at least until there's more evidence that it matters, the IOM concluded.

On the other hand, the Endocrine Society has called for regular screening for groups at risk for vitamin D deficiency such as the obese, African Americans, and pregnant women.

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